TRAF1 Coordinates Polyubiquitin Signaling to Enhance Epstein-Barr Virus LMP1-Mediated Growth and Survival Pathway Activation

H. Greenfeld, K. Takasaki, M. Walsh, I. Ersing, K. Bernhardt, Y. Ma, B. Fu, C. Ashbaugh, J. Cabo, S. Mollo, H. Zhou, S. Li, and B. Gewurz. PLOS Pathogens 11 (5): 1-35 (May 2015)


Author Summary The linear ubiquitin assembly complex (LUBAC) plays crucial roles in immune receptor-mediated NF-kB and MAP kinase pathway activation. Comparatively little is known about the extent to which microbial pathogens use LUBAC to activate downstream pathways. We demonstrate that TRAF1 enhances EBV oncoprotein LMP1 TES1/CTAR1 domain mediated MAP kinase and canonical NF-kB activation. LMP1 TES1 signaling induces association between TRAF1 and LUBAC, and triggers M1-polyubiquitin chain attachment to TRAF1 complexes. TRAF1 and LMP1 complexes are decorated by M1-polyubiquitin chains in LCL extracts. TRAF2 plays a key role in LMP1-induced LUBAC recruitment and M1-chain attachment to TRAF1 complexes. TRAF1 and LMP1 complexes are modified by lysine 63-linked polyubiquitin chains in LCL extracts, and TRAF2 is a target of LMP1-induced K63-ubiquitin chain attachment. Thus, the TRAF1:TRAF2 heterotrimer may coordinate ubiquitin signaling downstream of TES1. Depletion of TRAF1 or the LUBAC subunit HOIP impairs LCL growth and survival. Thus, although TRAF1 is the only TRAF without a RING finger ubiquitin ligase domain, TRAF1 nonetheless has important roles in ubiqutin-mediated signal transduction downstream of LMP1. Our work suggests that LUBAC is important for EBV-driven B-cell proliferation, and suggests that LUBAC may be a novel therapeutic target in EBV-associated lymphoproliferative disorders.

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